Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0010346 (Crohn's disease)
 21,615 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth hormone (GH) is used or is being evaluated for efficacy in treatment of short stature, aspects of aging, cardiac disorders, Crohn's disease, and short bowel syndrome. Therefore, we synthesized several stable growth hormone-releasing factor (GRF) analogues that could be therapeutically useful. One potent analog, [D-Ala(2),Aib(8, 18,)Ala(9, 15, 16, 22, 24-26,)Gab(27)]hGRF(1-27)NH(2) (GRF-6), with prolonged infusion caused severe diarrhea in monkeys; however, it had no side-effects in rats. Because GRF has similarity to VIP/PACAP and VIPomas cause diarrhea, this study investigated the ability of this and other GRF analogues to interact with the VIP/PACAP receptors. Rat VPAC(1)-R (rVPAC(1)-R), human VPAC(1)-R (hVPAC(1)-R), rVPAC(2)-R and hVPAC(2)-R stably transfected CHO and PANC 1 cells were made and T47D breast cancer cells containing native human VPAC(1)-R and AR4-2J cells containing PAC(1)-R were used. hGRF(1-29)NH(2) had low affinity for both rVPAC(1)-R and rVPAC(2)-R while VIP had a high affinity for both receptors. GRF-6 had a low affinity for both rVPAC(1)-R and rVPAC(2)-R and very low affinity for the rPAC(1)-R. VIP had a high affinity, whereas hGRF(1-29)NH(2) had a low affinity for both hVPAC(1)-R and hVPAC(2)-R. In contrast GRF-6, while having a low affinity for hVPAC(2)-R, had relatively higher affinity for the hVPAC(1)-R. In guinea pig pancreatic acini, all GRF analogues were full agonists at the VPAC(1)-R causing enzyme secretion. These results demonstrate that in contrast to native hGRF(1-29)NH(2,) GRF-6 has a relatively high affinity for the human VPAC(1)-R but not for the human VPAC(2)-R, rat VPAC(1)-R, rat VPAC(2)-R or rat PAC(1)-R. These results suggest that the substituted GRF analog, GRF-6, likely causes the diarrheal side-effects in monkeys by interacting with the VPAC(1)-R. Furthermore, they demonstrate significant species differences can exist for possible therapeutic peptide agonists of the VIP/PACAP/GRF receptor family and that it is essential that receptor affinity assessments be performed in human cells or from a closely related species.
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PMID:GI side-effects of a possible therapeutic GRF analogue in monkeys are likely due to VIP receptor agonist activity. 1144 45

Crohn's disease and ulcerative colitis are inflammatory diseases of the gastrointestinal tract characterized by chronic relapsing inflammation and catabolism. Growth hormone/insulin-like growth factor-I axis is important in inflammatory bowel disease, because of the effects on epithelial cell kinetics, collagen deposition and immunomodulation. The potential of growth hormone as a therapeutic option in inflammatory bowel disease has been proven in various clinical settings. Acquired growth hormone resistance in inflammatory bowel disease seems to be mediated by a combination of undernutrition and active inflammation. In particular, proinflammatory cytokines, such as TNF-a and interleukin-6, have been implicated as potential mediators of growth hormone resistance. The introduction of anti-TNF-alpha monoclonal antibodies has proven very efficacious in patients with inflammatory bowel disease. By reducing cytokines levels in inflammatory cells of intestinal mucosa, infliximab could interfere with cytokine-induced growth hormone resistance. Recent in vivo data have shown that acquired growth hormone resistance in patients with inflammatory bowel disease may be reversed after the administration of anti-TNF-alpha therapy.
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PMID:Growth hormone in inflammatory bowel disease. 1649 5

Growth hormone (GH) regulates anabolic metabolism via activation of the STAT5b transcription factor and reduces mucosal inflammation in colitis. Peroxisome proliferator-activated receptor (PPAR) gamma suppresses mucosal inflammation and is regulated by GH through STAT5b. We hypothesized that the GH:STAT5b axis influences susceptibility to colitis via regulation of local PPARgamma abundance. Colon biopsies from children with newly diagnosed Crohn's disease (CD) and controls were exposed to GH in short-term organ culture. Trinitrobenzene sulfonic acid (TNBS) administration was used to induce colitis in STAT5b-deficient mice and wild-type controls, with and without rosiglitazone pretreatment. GH receptor, STAT5b, PPARgamma, and nuclear factor kappaB activation and expression were determined. Epithelial cell GH receptor expression and GH-dependent STAT5b activation and PPARgamma expression were reduced in CD colon. STAT5b-deficient mice exhibited reduced basal PPARgamma nuclear abundance and developed more severe proximal colitis after TNBS administration. This was associated with a significant increase in mucosal nuclear factor kappaB activation at baseline and after TNBS administration. Rosiglitazone ameliorated colitis in wild-type mice but not STAT5b-deficient mice. GH-dependent STAT5b activation is impaired in affected CD colon and contributes to chronic mucosal inflammation via down-regulation of local PPARgamma expression. Therapeutic activation of the GH:STAT5b axis therefore represents a novel target for restoring both normal anabolic metabolism and mucosal tolerance in CD.
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PMID:Signal transducer and activator of transcription 5b promotes mucosal tolerance in pediatric Crohn's disease and murine colitis. 1714 64

Growth hormone (GH) exercises its growth effects by stimulating insulin-like growth factor I (IGF-I) synthesis in the liver (endocrine IGF-I) and by inducing chondrocyte differentiation/replication and local production of IGF-I (paracrine/autocrine IGF-I). Injectable recombinant human (rh)IGF-I (mecasermin) has been available for nearly 20 years for treatment of the rare instances of GH insensitivity caused by GH receptor defects or GH-inhibiting antibodies. Full restoration of normal growth, as occurs with rhGH replacement of GH deficiency, is not seen, presumably because only the endocrine deficiency is addressed. RhIGF-I has also been effective as an insulin-sensitizing agent in severe insulin-resistant conditions. Although the insulin-sensitizing effect may benefit both type 1 and type 2 diabetes, there are no ongoing clinical trials because of concern about risk of retinopathy and other complications. Promotion of rhIGF-I for treatment of idiopathic short stature has been intensive, with neither data nor rationale suggesting that there might be a better response than has been documented with rhGH. Other applications that have either been considered or are undergoing clinical trial are based on the ubiquitous tissue-building properties of IGF-I and include chronic liver disease, cystic fibrosis, wound healing, AIDS muscle wasting, burns, osteoporosis, Crohn's disease, anorexia nervosa, Werner syndrome, X-linked severe combined immunodeficiency, Alzheimer's disease, muscular dystrophy, amyotrophic lateral sclerosis, hearing loss prevention, spinal cord injury, cardiovascular protection, and prevention of retinopathy of prematurity. The most frequent side effect is hypoglycemia, which is readily controlled by administration with meals. Other common adverse effects involve hyperplasia of lymphoid tissue, which may require tonsillectomy/adenoidectomy, accumulation of body fat, and coarsening of facies. The anti-apoptotic properties of IGF-I are implicated in cancer pathogenesis-a concern for long-term therapy. It is unlikely that mecasermin will be useful beyond the orphan indications of severe insulin resistance and GH insensitivity.
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PMID:Mecasermin (recombinant human insulin-like growth factor I). 1919 69

Crohn's disease in childhood causes linear growth retardation, which has a substantial effect on management of this disease. By contrast, growth is rarely a problem in children presenting with ulcerative colitis. Depending on how growth failure is defined, approximately one-third of children with Crohn's disease have growth retardation at diagnosis. Although corticosteroids can suppress growth, decreased height at diagnosis demonstrates that this finding is a consequence of the disease and not merely an adverse effect of treatment. Both inflammation and undernutrition contribute to decreased height velocity. Increased cytokine production acts both on the hepatic expression of insulin-like growth factor 1 (IGF-1) and at chondrocytes of the growth plates of long bones. Growth hormone insensitivity caused by deranged immune function is a major mechanism in growth retardation. Resolution of inflammation is the cornerstone of treatment, but current studies on growth hormone and IGF-1 might yield therapies for those children whose inflammation is refractory to treatment.
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PMID:Growth problems in children with IBD. 2495 8